Peripheral and central IGF-1 action in energy balance and longevity modulation

外周和中枢 IGF-1 在能量平衡和寿命调节中的作用

• 批准号: 8655133
• 负责人: DEREK Major HUFFMAN
• 金额: $ 24.65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8655133
• 关键词: Accounting; Acute; Aging; Animal Model; Animals; Applications Grants; Award; Body fat; Brain; Cardiac; Cardiovascular Diseases; Cause of Death; Central obesity; Chronic; Clinical; Clinical assessments; Collaborations; Complex; Data; Development; Development Plans; Energy Metabolism; Environment; Equilibrium; Exercise; Fatty acid glycerol esters; Funding; Gene Expression; Genetic; Genetically Engineered Mouse; Glucose; Goals; Health; Homeostasis; Human; Hybrids; Hypothalamic structure; Inbred BN Rats; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Knock-out; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Mentors; Metabolism; Modeling; Morbidity - disease rate; Neuraxis; Neurobiology; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Osteoporosis; Pathologic; Peripheral; Phase; Principal Investigator; Pump; Rattus; Research; Research Personnel; Research Training; Risk; Role; Secure; Signal Transduction; Site; Somatotropin; Students; Subfamily lentivirinae; Technology; Testing; Time; Training; Viral; Visceral; Work; cancer risk; cancer therapy; career; career development; cognitive function; cohort; design; energy balance; frailty; glucose metabolism; healthy aging; improved; in vivo; insight; male; mortality; mouse model; novel; overexpression; post-doctoral training; receptor; research study

Proposal Summary The immediate career goal of this candidate is to expedite the research currently being conducted as part of his postdoctoral training and to enhance his career development to enable his successful transition to an independent career in aging research. The current and proposed research is focused on distinguishing the central and peripheral effects of IGF-1 on energy balance, insulin action, healthy aging and longevity. As such, this proposal will require that the candidate develops and enhances his training in both genetics and neuroscience in order to successfully engage some facets of this proposal. In collaboration with his mentor, a 5-year career development plan has been designed which in the short-term will focus on intensive course work and hands-on training in genetics and neurobiology, and a mentoring committee of neuroscientists that will help to oversee the candidate's research and training. The long-term career goals of this proposal are to enable the candidate, as a new principal investigator, to secure protected time to develop his research team, to enhance his ability to train fellows and students, establish new collaborations and develop a novel line of research which produces strong grant proposals to secure independent funding. The candidate and his lab have recently uncovered remarkable positive effects of central IGF-1 action including improved peripheral insulin action and selective depletion of visceral fat, suggesting novel actions that are favorable for aging. This is in contrast to peripheral IGF-1, where among its good effects are also 'bad' effects, such as raising cancer risk. In this proposal, we will attempt to further dissect the 'good' and 'bad' effects of IGF-1 on aging, including central versus peripheral effects. The overall hypothesis of the research plan is that healthy aging and longevity is best achieved by increasing IGF-1 action in the hypothalamus to reap the 'good' effects while decreasing it in the periphery to minimize the 'bad' effects, namely cancers. Ultimately, these studies may yield important new insights regarding the complex role of IGF-1 on health and aging with relevance to humans. The candidate has devised three specific aims to be performed during the award period in order to test the overall hypothesis. Aim 1 of this proposal will focus on distinguishing between the central versus peripheral effects of acute IGF-1 action in regulating peripheral glucose metabolism with aging and will work toward establishing the mechanism(s) in the hypothalamus utilizing a combination of strategies including the use of novel genetically-engineered mice. Aim 2 of this proposal will focus on distinguishing between the central and peripheral effects of chronic IGF-1 action in regulating glucose and energy homeostasis with aging and will utilize both the rat model and a mouse model of inducible IGF-1 overexpression in the brain. The goal of Aim 3 will be to study the lifelong effects of chronic central IGF-1 overexpression by lentivirus targeted to the mediobasal hypothalamus and/or lifelong peripheral IGF-1 receptor blockade on healthy aging and longevity in rats. At the conclusion of the K99/R00 award, the candidate expects to have achieved his short-term and long-term career goals and to have elucidated novel and significant mechanisms relevant to IGF- 1 action and aging.

提案摘要 该候选人的近期职业目标是加快目前正在进行的研究 作为博士后培训的一部分，并促进他的职业发展，使他能够取得成功 过渡到衰老研究的独立职业。当前和拟议的研究重点是 区分 IGF-1 对能量平衡、胰岛素作用、健康的中枢和外周影响 衰老和长寿。因此，该提案将要求候选人发展并增强他的能力 遗传学和神经科学方面的培训，以便成功地参与其中的某些方面 提议。与导师合作，设计了5年职业发展计划 短期内将侧重于遗传学和遗传学方面的强化课程工作和实践培训 神经生物学，以及一个由神经科学家组成的指导委员会，将帮助监督候选人的 研究和培训。该提案的长期职业目标是使候选人能够成为 新的首席研究员，以确保有受保护的时间来发展他的研究团队，提高他的研究能力 培训研究员和学生、建立新的合作和开发新颖的研究方向的能力 它提出了强有力的赠款提案以确保独立资金。候选人和他的实验室 最近发现中枢 IGF-1 作用具有显着的积极作用，包括改善 外周胰岛素作用和内脏脂肪的选择性消耗，表明新的作用 有利于衰老。这与外周 IGF-1 形成鲜明对比，其良好作用还包括 “坏”影响，例如增加癌症风险。在这个提案中，我们将尝试进一步剖析“好” IGF-1 对衰老的“不良”影响，包括中枢与外周的影响。整体 该研究计划的假设是，实现健康老龄化和长寿的最佳方法是 增加下丘脑中 IGF-1 的作用以获得“良好”效果，同时减少下丘脑中 IGF-1 的作用 外围以尽量减少“坏”影响，即癌症。最终，这些研究可能会产生 关于 IGF-1 对健康和衰老的复杂作用的重要新见解 人类。候选人制定了三个在颁奖期间要实现的具体目标 以便检验总体假设。该提案的目标 1 将侧重于区分 IGF-1 急性作用调节外周葡萄糖代谢的中枢与外周效应 随着衰老，并将致力于利用下丘脑建立机制 多种策略的组合，包括使用新型基因工程小鼠。这个目标2 该提案将重点关注区分慢性 IGF-1 的中枢效应和外周效应 随着衰老调节葡萄糖和能量稳态的作用，并将利用大鼠模型和 大脑中诱导型 IGF-1 过度表达的小鼠模型。目标 3 的目标是研究 慢病毒靶向中基底层慢性中枢IGF-1过度表达的终生影响 下丘脑和/或终生外周 IGF-1 受体阻断对健康衰老和长寿的影响 老鼠。在 K99/R00 奖项结束时，候选人预计已实现其短期目标 和长期职业目标，并阐明了与 IGF-相关的新颖且重要的机制 1动作与老化。